2-(b-aminoethylsulfonylamine)thiazole

ABSTRACT

Aminoethanesulfonyl derivatives having a general formula RSO2CH2CH2Y where R is selected from a group consisting of thiazolyl-2-amino, 1-pyrrolyl, 4-methylpiperazyl, and 1-indolyl and Y is NH2 or, when R is thiazolyl-2-amino, said Y may be nicotinoylamino as well as manufacture methods thereof were disclosed.

United States Patent [191 I Aug. 27, 1970 Aug. 27, 1970 Aug. 27, 1970 Dec. 18, 1970 Dec. 18, 1970 group consisting of thiazolyl-Z-amino,

Naito June 28, 1974 Z-(B-AMINOETHYLSULFONYLAMINE) [52] U.S. Cl 260/3063 R THIAZOLE [51] Int. Cl C07d 91/34 I [76] Inventor: ShunJchi Nam), 5 Mumsakino [58] Field of Search 260/306.8 R i zl Kltaku Kyoto [56] References Cited UNITED STATES PATENTS [22] 1972 3,743,647 7/1973 Naito 260/3061; R [21] Appl. No.: 311,278

. Related Us Application Data Primary ExaminerR. J. Gallagher 1 I3Di7 lS3iOg14ofSer. N0. 164,007,July 19, 1971, Pat. No. [57]. ABSTRACT I Aminoethanesulfonyl derivatives having a general for- [30] Foreign Application p i i Data mula R-SO CH CH Y where R is selected from a l-pyrrolyl, 4-methylpiperazyl, and l-indolyl and Y is NH or, when R is thiazolyl-Z-amino, said Y may be nicotinoylamino as well as manufacture methods thereof were disclosed.

2 Claims, No Drawings 1 2-(B-AMINOETHYLSULFONYLAMINE) MCIHLAZQLE- This is a division of application Ser. No. 164,007 filed July 19, 1971, now US. Pat. No. 3,743,647.

The present invention relates to aminoethanesulfonyl derivatives of the general formula R SO CH C1-1 Y in which R is selected from a group consisting of and Y is N11 In case R is thiazolyl-2-amino, the Y may also be nicotinoyl-amino. This invention also relates to manufacturing methods for these aminoethanesulfonyl derivatives.

All of these aminoethanesulfonyl derivatives are novel compounds having never been disclosed in any literature including patent specification. They are useful as medicines, such as analgesics, .with little side effects. These compounds are characterized by containing taurine which is one of amino acids and has surface activity as well as analgesic action and, when they are given to human beings, their effects are now lowered even when subjected to a detoxication reaction in vivo such as an acetylation. Furthermore, some of these compounds are also useful as anti-histaminic, hypocholesterolemic and anti-inflammatory drugs.

Although the compounds of this invention have considerable water solubility, they are resistant to moisture to such an extent that, even when they are allowed to stand in an open container placed in a room for one year, more than 90 percent of the content remains unchanged in most cases indicating little absorption of moisture. In addition, the aqueous solution thereof is also stable. Thus, for example, when a 5 percent aqueous solution of them is allowed to stand at room temperature for one year, more than 90-95 percent thereof remains unchanged. This is practically advantageous, particularly in view of use of the compounds in injection.

Compounds of this invention can be manufactured by various routes which will be explained in detail.

Thus, for example, compounds nicotinoylamino group can be manufactured by nicotinoylation of the corresponding amino compounds or by nicotinoylamination of the corresponding halides. The latter method (nicotinoylamination of halides) will be disclosed later in an item of amination reaction.

The former method, i.e., nicotinoylation of aminoethanesulfonylaminothiazole (1), may be represented as:

where Y is 1 NHSOzCHaCHzNHz In order to carry out the present nicotinoylation, any of known method for nicotinoylation may be employed. It is preferred to effect the nicotinolylation by use of acids bearing a nicotinoyl group or the functional derivatives thereof such as acid anhydrides, acid esters, acid halides or the mixtures thereof. These acids and their functional derivatives may also be employed in the form of their salts. The reaction may be Carried out at either normal temperature or with heating and under normal pressures or pressures above normal, depending upon the kinds, quantities or the like of the reactants used. Furthermore the starting material (1) of the present reaction may be employed in its salt form.

The present method will be further explained in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method used only to illustrate but not limit the invention.

EXAMPLE 1 Into 0.1 mole of the starting material or its hydrochloride is added from 100 to 200 ml. of anhydrous pyridine with subsequent addition of nicotinic acid chloride hydrochloride (0.1 mole). After heating the mixture for an hour, or, alternatively, standing the same whole day at a room temperature, the mixture is heated for an additional one hour. The pyridine is distilled off under reduced pressure from the reaction mixture, the residue recrystallized several times from either methanol or from ethanol to obtain the desired product (11) as its hydrochloride having a melting point of 289C (Colorless needles). lnto said residue from which the pyridine has been distilled off is added water and the mixture is made alkaline (pH about 9)' byuse of aqueous ammonia (of about 28 percent). The resulting mixture is evaporated under reduced pressure to dryness and the residue recrystallized several times from water to obtain the desired product (11) as colorless needles having a melting point of 228C. The yields of the desired product and its hydrochloride are almost identical and within the range of from about to percent of the theory.

Element Analysis Desired product (11) Calculated for C, H N,O S C 42.31; H 3.85; N I

chloride can proceeds also in water or various organic solvents, as well as in pyridine and that it also proceeds advantageously when a small quantity of pyridine or al-- kali is added into the water or various organic solvents.

For example, 0.] mole of the starting material (I) or its hydrochloride is charged with 500 ml. of ethyl ace-f tate, into which mixture O;l mole of nicotinic acid chloride hydrochloride is added followed by heating under reflux in water bath for 3 hours. After distilling off the ethyl acetate from the reaction mixture remain yellowish solids, which are then recryallized from ethanol or methanol to obtain the hydrochloride of the desired product (ll). Alternatively, said residual solids are dissolved in a small amount of water, which solution is made alkaline by use of ammonia (pH about 9) and distilled under reduced pressure to remove the water. The residue is recrystallized from water to obtain the desire product (II) in its pure form. In this case, the yield was little different from that obtained in the case of employment of pyridine as solvent.

In addition, in the following examples 2 and 3' are shown the embodiments of theinvention wherein nicotinic acid anhydride and nicotinic acid are employed in place of nicotinic acid chloride(hydrochloride) used in Example 1..

EXAMPLE 2 Into a 100 ml. three-necked flask are placed 0.1 mole of the starting material (I), 0.1 mole of nicotinic acid anhydride and 100 ml of anhydrous pyridine folloed by heating the mixture on boiling water bath with agitation for ,7 hours. The pyridine is distilled off under reduced pressure and to the residue is added strong aqueous ammonia (of about 28 percent) to make it alkaline, whereupon yellowish-white substance precipitates. The mixture is, as such, subjected to distillation under resuced pressure to remove the water, the residue recrystallized several times from water to obtain the desired product (II) in its pure form. The crystals, when subjected to mixed examination using the corresponding standard, show no lowering in their melting point. The yield is about 70 percent.

EXAMPLE 3 sure, the residue being made alkaline (pH about 9) by use of strong aqueous ammonia followed by distilling off the water under reduced pressure. The residue is recrystallized several times from water to obtain the pure desired product (II). The product, when sibjected to mixed examination using the corresponding standard material, show no lowering in its melting point. The yield is about 65 percent.

Referring now by way of precaution, the method according to the present invention can also be effected by proceeding the reaction in the presence of catalyst. Nicotinoylaminoethane-sulfonylaminothiazolw (ll) contains, in its structure, a pyridine ring of nicotinic acid and, since the nitrogen atom in said ring is basic, it may be, of course, optionally reacted with any organic or inorganic acid to form the corresponding acid addition salt. Subsequently, in order to purify the end product, there may be employed, as well as the hydrochloride. any organic salts as for example, its fumarate, flavianate or tartarate. For example, the end product (ll) may be readily purified by forming its hydrochloride by either adding thereto concentrated hydrochloric acid followed by evaporation under reduced pressure to dryness or introducing gaseous HCl into asolution of .the desired product (II) in methanol or ethanol, with subsequent recrystallization of the hydrochloride from methanol or ethanol.

The above disclosure is an explanation in detail of a method to manufacture nicotinoylamino compounds by nicotinoylation of the corresponding amino compounds.

Compounds of the present invention in which Y is an amino radical can be manufactured by the following two methods:

l. Amination of the corresponding halides 2. Deacylation of the corresponding acylamino (or acylimino) compounds The amination according to l will be expalined at first together with a nicotinoylamination of the corresponding halides for the sake of convenience.

Said a mination method can be accomplished by the reaction of the halide of the formula R SO CH CH Z (where R is as defined'already; Z is halogen) with monia or nicotinic acid amide. v

The halogen designated by Z in the above-described formula is preferably chlorine, bromine or iodine, of which chlorine is particularly preferred.

The ammonia or nicotinic acid amide to be reacted may be used as such or after dissolving or suspending in water and/or oga organicsolvent, and its salts with acids may also be employed, if desired. The reaction in accordance with the present invention may proceeds under normal pressure, although it is preferred to carry out the reaction under pressure above normal, in which case it is more preferred to effect the reaction in the presence of catalyst as for example, Nal, Cu Cl NHJ or the like compound.

The halides to be employed as the starting materials according to the present invention are also novel compounds having been described in no literature and may be prepared, for example, by reacting Z-aminothiazole, N-methylpiperazine, pyrrole or indole with haloethylsulfonyl halide.

The present invention will be further described in de tall with particular reference to the following examples, but it will be understood that these examples be preferrcd embodiments of the present invention and the invention he never limited thereto.

Example 4 (Y NH 10 G. of the compound of the formula (III) wherein X is Cl is reacted in an autoclave in the presence of catalyst with either anhydrous ammonia or with ammonium carbonate and aqueous ammonia by heating the reactants. After completion of the reaction, the contents are made acidicby useof hydrochloric acid, the resulting precipitates removed by filtering off the same under sunction, the filtrate evaporated under reduced pressure to dryness and the residue recrystallized from quantities of ethanol to obtain the hydrochloride of the desired product. Alternatively, the said filtrate is made alkaline by use of strong aqueous ammonia (to pH (ill) about 9) followed by evaporation under-reduced pressure to dryness, the residue recrystallized from either water or from a mixture of water and acetone to obtain the desired product. The melting points and details of the reaction conditions are shown in Table 2, while the 5 element analysis in Table 3.

TABLE 1 MI. 01 the rloslrerl M.P. 01 the hydrochloride of the 10 Note When the above-described reaction was repeated except that there was EXAMPLE 5 (Y Nicotinoylamino) (c) To 5 g. of the compound of the formula (11) wherein R is thiazolyl and Z is Cl is added 8 g. of nicotinic acid amide or its hydrochloride, and the mixture is reacted, in an autoclave, in the presence of 3 g. of Cu C1 at a temperature of 100 C for about 6 hours. The contents are thereafter made acidic by use of hydrochloric acid. the precipitates formed thereny filtered off under sunction. The filtrate is evaporated under reduced pressure 1t product desired product to dryness, the residue recrystallized from methanol or My M520 MR ethanol to obtain the hydrochloride of the desired UHa-N (colored and (colored and product (i.e., nicotinoylaminoethanesulfonylaminocomposed). Colorcomposed). Colorless crystals. less crystals. 111132016 hydrochloride (1a)" Altemativel the filtrate as described above is made 15 y 1143-1552-3156 343-319-322 alkaline by use of ammonia and evaporated under re- N- (colored and de- (colored and decomposed). Colorcomposed). Colorduced pressure to dryness, the residue being recrystal- (Im crystals less crystals lized from water to obtain the desired product as color- -N MR 325382 My. 21 Colorless less needles. Yteld about percent. Its molecular l (colored and decrystals. 20 weight and element analysts are shown tn Table 3. As $353, 33, 9 in Example 4, there resulted some reduction in yield 5/ when there was employed, as the starting material, the (Id). bromide (Z=Br) or iodide (Z=I) or no catalysts were M.P. 323-32s M.P. 258-264 P Qy (colored and (comma and 2 The destred product wherein R is thtazo1y1-2-amtno composed). composed). 5 o

and Y 15 ntcottnoylammo) has a melting potnt of 229 C N and the hydrochloride thereof of 288C.

Table 2 Starting amine Reaction Temperature Yield (7:) Catalst and time(Hrs.) (C) M the added amount 1a 1b 1d 1e thereof (6.).

Anhydrous ammonia! 20) 5 100 43 36 40 Nal(0.45) do. (20) 5 52 45 40 48 cuzctltto) Na CO l0) 28 %NH,OH(20m1.) 8 38 34 30 3s Cu Cl (0.4)

employed. as the starting material, the

bromide (X=Br) or iodide (X=1) in place of the chluride(X=C1). there resulted some reduction in yields. Similar reduction in yields ocurred also when using no catalysts.

Table 3 Compounds Molecular formulas Calculated Found la C H, N O S C 40.58 C 40.65 (N-methylpiperazine family) H 8.21 H 8.18 N 20.29 N 20.20 1a( hydrochloride) C H N O SC1 C 26.50 C 26.72' (N-methylpiperazine family) 7 {H 6.31 H 6.28 N 13.25 N 13.33 lb C H N O S C 41.38'v C 41.25 (pyrrole family) {H 5.74 H 5.82 N 16.09 N 16.21 1b(hydrochloride) C H, N,O SC1, C 29.15 C 29.28 (pyrrole family) {H 4.87 H 4.76 N l 1.34 N 1 1 .42 1c C H N O S C 42.31 C 42.38 (thiazole family) {H 3.85 H 3.91 N 17.95 N 17.72 lc(hydroch1oride) C H N,O;,S CI C 34.29 C 34.31 (thiazole family) H 3.64 H 3.60 N 14.55 N 14.47 1d 7 C H N O S, C 28.99 C 29.12 (thiazole family) {H 4.35 H 4.21 N 20.29 N 20.34 1d (hydrochloride) C H N O,S C1 C 21.43 C 21.38 (thiazole family) {H 3.93 v H 3.99 N 15.00 N 15.23 1e C wH gNgogs C. 53.57 C 53.63 (indolyl family) H 5.36 H 5.28 N 12.51) N 12.63 1e (hydrochloride) C H N O SCI C 46.07 C 46.1 1 {H 4.99 H 4.89 N 10.75 N 10.68

(indolyl family) The above is an explanation as to the manufacture of the desired compounds by amination (and lized from either water or from a mixture of water and acetone and the resulting crystals, together with the previously stored crystals, being recrystallized several times from either water or from a mixture of water and acetone to obtain the desired produce as colorless crystals. The details of these reactions are shown in Table Similar procedures are repeated except that there are employed, as the starting material, ones wherein Q is benzoylamino or acetylamino group, the corresponding desired products are obtained in yields as tabulated in Table 5. The element analysis of the desired products thus obtained are shown in Table 6.

pionylamino groups, as well as aromatic amino groups TABLE' such as benzoylamino and nicotinoylamino groups. Preferred example of the acylimino group is Amount phthalimino group. Of course, these specific examples $323 3; of the acylamino and acylimino groups are mentioned solution M.P. or the desired Yield only by way of example to explain the present inven- R (10 added (mm product tion. Therefore it will be understood that the present 50 MR (601m (1 32 invention be by no means restricted to employment of HaC-N N and decomposed). such specific examples.

The above-described hydrolysis may be effected ad 50 a r iifgi i l ilg i 3'0 vantageously 1n any known manner where there are employed, for example, acids, sodium alcoholate, alkali 40 MR (colored metal hydroxides, alkali metal carbonates or the like and materials. In particular, preferred results may be ob- V'L tained in the present invention when a concentrated solution of alkali metal hydroxide such as NaOH or KOH. l

N 40 M.P. 325332 (colored 2.3 When the deacyaltion of the invention is to be ef- L anddecomposed) fected by hydrazinolysis, there may be employed any S known method for it, such as one wherein hydrazine hydrate is added into a methanolic or ethanolic solu- WW tion with subsequent treatment with hydrochloric acid.

- All of the resulting products are in the form of color- Starting materials in this method are also novel com- Crystalspounds having never been described in any literature and may be prepared, for example, by the reaction of 40 N-methylpiperazine, pyrrole, indole or 2-aminothiazole TABLE 5 with an acylaminoethanesulfonyl halide. Yield The present method will be further illustrated in de- R I Q (g-) tail with particular reference to the following examples, v l but it will be understood that these examples be pre- CHPN iggg lg ff i2? ferred embodiments of the present method and the present invention be never limited thereto. Phthalimino 10 4.0 l N Acetamino. 10 4. 3 EXAMPLE 6 Into the starting material where Q is phthalimino igggiiii iifi jjjjjjjj iii 2:; group is added a 30 w/v percent solution of hydroxide i followed by boiling the mixture under reflux for 3 5 J hours. After cooling the mixture is made acidic by use I of concentrated hydrochloric acid while ice-cooling, N Phthanmmm 10 M and'then ad usted to a pH of about 9 by addltlon of so- I 10 dium carbonate. The crystals precipitated thereby are L separately stored. The filtrate is evaporated under res duced pressure to dryness, the residue being recrystal- TABLE 6 Percent Calculated Found Molecular R formula (3 II N C ll N C1H17N3O2S 40.58 s. 21 20. 20 40.67 8.18 20.33 HaCN N- CUHIIJNZOES 41.38 5.74 10.09 41.25 5.83 10. 22

TABLE 6- Con1inued Percent Calculated Found Molecular R formula C .H N C H N C1oH12N202S 53.57 5.36 12. 50 53.68 5 38 12.60

FT'L C5H9N302S2 28.09 4. 35 20.20 29.05 4.30 20.38 NH- EXAMPLE 6 said filtrate is evaporated under reduced pressure to To the starting material wherein Q is phthalimino.

group is addedfrom about 5 'to 8 times its volume of 95 percent ethanol followed by the addition of 1.1 times its molar amount of hydrazine hydrate (of about 100 percent). The mixture .is heated under reflux for about 2 hours with continuous stirring. Thereafter, the mixture is adjusted to a pH of about 1 by the addition of hydrochloric acid, heated on water bath for further about 30 minutes and filterred in. hot to remove the precipitated phthalic acid hydrazide, the filtrate being cooled to precipitate the hydrochloride of the desired product which is then filtered and then recrystallized several times to purify the same. [Alternati /ely the dryness and the residue is made alkaline (pH about 9) by the addition of a Na CO solution followed by evaporating again under reduced pressure to dryness. The residue is recrystallyzed several times from water or from a mixture of water and acetone to obtain the free desired product] The details of the reactions are shown in Table 7. lnaddition, the element analysis of the hydrochloride of the desired product is shown in Table 8.

By the way, when, in Example 6, sodium carbonate is employed to make the reaction mixture alkaline, the

hydrochloride asobtained in this example may be also obtained by reducing the amount thereof added and thereby making the mixture weakly acidic.

TABLE 7 Amount Amount of the of Solvent used starting hydrazine for recr stalrnaterial hydrate 7 Yield lizlngt e R used (g) (g.) MI. of the HCl salt of the desired product (g.) H01 salt 130 I 22 MP. 318-319" (colored and decomposed)..."....... n2 Etlmnol. CHa-N N- 122 22 MP. 319-322 (colored and decomposed) Do. N-

M.P. 258-264 (colored and decomposed) c Do.

- M.P. 325-332 (colored and decomposed) Methanol.

lL L H M TABLE 8 Percent Calculated Found Molecular R formula C H N C II N I C H: N OaSCl 26. 6.31 13. 2' 26.43 6.45 13. 38 cm-N N 7 0 3 J CoHUNzOzSCl 29.15 4.57 11.34 29. 27 4,78 11. 45

CmHnNzOzSCl 46.07 4.99 10.75 46.11 4.87 10.82

We claim: thereof. 1. A compound of the formula: 2. The compound according to claim 1 which has the o m l s I NHso,cH,cH, -NH, N

s H: NHs0;cH,cH, H, N r r,l.,fl --w and thc pharmaceutically acceptable acid addition salt s Disclaimer 3,821,238.S7mm-I0hi Naito, Kyoto, J apan. Q-(B-AMINOETHYLSUL- FONYLAMINO)THIAZOLE. Patent dated June 28, 1974. Disclaimer filed Feb. 6, 1975, by the inventor. The term of this patent subsequent to Dec. 3,

[Oyficial Gazette July 15, 1975.]

1991, has been disclaimcd. 

2. The compound according to claim 1 which has the formula: 